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  • Review Article
  • Published:

Transcriptional determination and functional specificity of myeloid cells: making sense of diversity

Nature Reviews Immunology volume 17, pages 595–607 (2017)Cite this article

Subjects

Key Points

  • Innate immune responses to an invading pathogen involve different cell types that have distinct functional properties.

  • Specific transcriptional and post-transcriptional mechanisms affect responses to danger signals in individual cell types.

  • The combinatorial activity of a limited number of transcription factors with broadly overlapping expression profiles is crucial during myeloid cell differentiation.

  • Recent data from single-cell genomics have contributed to revising developmental trajectories in the myeloid compartment.

  • Different myeloid cells can have highly specific responses to the same danger signal.

  • The mechanisms behind distinct functional outcomes in response to similar signals require further investigation.

Abstract

Early responses to invading pathogens and to non-microbial danger signals are mediated by different innate immune and parenchymal tissue cells, which are able to respond to a variety of pathogen- and danger-associated molecular patterns. In most if not all instances, innate immune responses to a given molecule are not uniquely confined to one responding cell type, but instead involve the engagement of different cells with intrinsically distinct properties. In this Review, we discuss the molecular basis of the differentiation of myeloid cells, which is controlled by transcription factors, transcriptional co-regulators and post-transcriptional mechanisms, and examine how the functional specification of the resulting mature immune cells of the myeloid lineage affects their response to danger signals.

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Figure 1: A unique combination of active (or poised-for-activity) enhancers in each specific cell type contributes to the establishment of cell identity.
Figure 2: Transcription factor accessibility regulates gene expression.
Figure 3: Transcriptional modules involved in the differentiation of myeloid cells.
Figure 4: Engagement of receptors by pathogens leads to different outcomes and effector functions in various myeloid cells.

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Acknowledgements

Work in the S.M. laboratory on this topic is funded by the Swiss National Science Foundation (156875). Work in the G.N. laboratory on this topic is funded by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement number 692789) and the Cariplo Foundation (grant 2015–0584).

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Authors and Affiliations

  1. Institute for Research in Biomedicine, Via Vincenzo Vela 6, Bellinzona, CH-6500, Switzerland

    Silvia Monticelli

  2. Department of Biomedical Sciences, Humanitas University, Via Manzoni 113, Rozzano (Milan), 20089, Italy

    Gioacchino Natoli

  3. Department of Experimental Medicine, European Institute of Oncology (IEO), Via Adamello 16, Milan, 20139, Italy

    Gioacchino Natoli

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  1. Silvia Monticelli
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Correspondence to Silvia Monticelli or Gioacchino Natoli.

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PowerPoint slides

Glossary

Extracellular traps

First reported to be produced by neutrophils, extracellular traps are a meshwork of extruded chromatin fibres (containing DNA and histone proteins) as well as antimicrobial peptides and various enzymes. Subsequently discovered to also be produced by other innate cell types and considered important for immobilizing and killing invading pathogens.

Promoters

Genomic regions usually extending a few hundred base pairs upstream of the transcription start site of a given gene; contain sequence elements (motifs) for transcription factor binding, as well as a 'core promoter' required for the assembly of the RNA polymerase II basal transcription machinery.

Enhancers

Contain arrays of binding sites for transcription factors. They act on transcription by working in conjunction with promoters, but can be located up to 1 Mb from the genes that they regulate.

Histone modifications

Covalent post-translational modifications of the nucleosomal histone proteins around which DNA is wrapped. Including methylation, acetylation and phosphorylation, they occur predominantly at the amino-terminal tails (∼40 amino acids) of the histone proteins and influence gene transcription.

M1 macrophages

(also known as classically activated macrophages). Distinguished from M2 (alternatively activated macrophages) based on the signals that they receive and the type of effector functions that they elicit. Activated by interferon-γ (IFNγ) and associated with a prototypical pro-inflammatory and microbicidal response.

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Monticelli, S., Natoli, G. Transcriptional determination and functional specificity of myeloid cells: making sense of diversity. Nat Rev Immunol 17, 595–607 (2017). https://doi.org/10.1038/nri.2017.51

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